Quinolones as antibacterial agents

ABSTRACT

A novel series of quinolone carboxylic acids for use as antibacterial agents are described. Methods for making the compounds, methods of using the compounds and compositions containing them are also described. Certain novel intermediates are also described.

This is a divisional of U.S. application Ser. No. 083,532 filed Aug. 7,1987, now U.S. Pat. No. 4,780,468.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 4,341,784 discloses certain substituted7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacids having the general formula: ##STR1##

The Journal of Medicinal Chemistry, 23, 1358 (1980) discloses certainsubstituted 3-quinolinecarboxylic acids having the structural formula##STR2## wherein ##STR3## may be pyrrolidinyl. See also U.S. Pat. No.4,146,719.

Certain 7-heterocyclic substituted 1,8-naphthyridines are disclosed inEur. J. Med. Chem.-Chimica Therapeutica, 29, 27 (1977). U.S. Pat. Nos.3,753,993, 3,907,808, and U.S. Pat. No. 4,604,401 disclose certain7-pyridylquinolines.

European Application No. 184,384 discloses certain substituteddihydroquinoline derivatives having the formula ##STR4## wherein in partR₁ is hydrogen, 1-6C alkyl, benzyl, or a pharmaceutically acceptablecation; R₂ may be hydrogen or fluorine, R₃ an optionally substitutedphenyl; and Y optionally substituted 1-3C alkyl, hydroxyethyl,cyclopropyl, vinyl, allyl or phenyl.

The references teach that these compounds possess antibacterialactivity.

SUMMARY

One aspect of the present invention is a compound of formula ##STR5##wherein R₁ is hydrogen, an alkyl of from one to six carbon atoms or acation;

R₂ is alkyl of from one to four carbon atoms, vinyl, haloalkyl orhydroxyalkyl of from one to four carbon atoms or cycloalkyl of fromthree to six carbon atoms;

Y is hydrogen, fluoro or amino;

Z is ##STR6## wherein n is 1, 2, 3, or 4;

n' is 1, 2, 3, or 4;

n+n' is a total of 2, 3, 4, or 5;

n" is 0, 1, or 2;

n'" is 0, 1, or 2;

n^(1v) is 1, 2, or 3;

n² is 0 or 1;

R₃ is hydrogen, alkyl of from one to four carbon atoms or a cycloalkylof from three to six carbon atoms;

R₄ is hydrogen, alkyl of from one to four carbon atoms, hydroxyalkyl offrom two to four carbon atoms, trifluoroethyl, or R₄ 'CO wherein R₄ ' isalkyl of from one to four carbon atoms, or alkoxy of from one to fourcarbon atoms;

R₅ and R₆ are each independently hydrogen or alkyl of from one to threecarbon atoms;

R₇ is hydrogen, alkyl of from one to three carbon atoms, hydroxyalkyl offrom two to three carbon atoms, benzyl, or p-aminobenzyl;

R₈ and R₉ are each independently hydrogen, alkanoyl of from one to threecarbon atoms, alkyl of from one to three carbon atoms, isopropyl orcyclopropyl;

R₁₀ and R₁₁ are each independently hydrogen, methyl, ethyl, or benzyl;

R₁₂, R₁₃, and R₁₄ are each independently hydrogen or methyl;

R₁₅ is methyl, ethyl, or isopropyl;

R₁₆ is CH₂ OR₁₈, CH₂ NR₁₈ R₁₉, or NR₁₈ R₁₉ wherein R₁₈ and R₁₉ arehydrogen, alkyl of from one to three carbon atoms, acyl of from one tothree carbon atoms;

R₁₇ is absent, hydrogen or alkyl of from one to three carbon atoms;

R₂ wherein the dotted line means a single or double bond;

R₂₀ and R₂₁ are each independently hydrogen, halogen, NR₂₂ R₂₃, OR₂₂,sR₂₂, alkyl of from one to three carbon atoms, wherein R₂₂ and R₂₃ areeach independently hydrogen, alkyl of from one to three carbon atoms, oracyl of from one to three carbon atoms;

or a pharmaceutically acceptable acid addition or base salt thereof.

The preferred compounds of this invention are those wherein R₂ is ethyl,vinyl, 2-fluoroethyl, difluoroethyl, or cyclopropyl.

Also preferred compounds of this invention are those wherein Z is##STR7##

Other preferred compounds of this invention are those wherein R₁ ishydrogen or a pharmaceutically acceptable base salt such as a metal oran amine salt.

Other preferred compounds of this invention are those wherein n" is one,R₃, R₅, and R₆ are hydrogen, methyl, ethyl, or n-propyl, and R₄ ishydrogen.

The most preferred compounds are those wherein Z is ##STR8## wherein R₁is hydrogen, R₂ is ethyl, vinyl, 2-fluoroethyl, or cyclopropyl, and R₃is hydrogen, methyl, ethyl, 1-propyl, 2-propyl, R₅ and R₆ are hydrogenor methyl, or a pharmaceutically acceptable acid addition or base saltthereof.

Additionally the most preferred compounds include those wherein R₂ iscyclopropyl, Z is ##STR9## in which n" is 0 or 1 and R₃ is hydrogen,methyl, ethyl, 1-propyl, 2-propyl, R₅ and R₆ are hydrogen or methyl, andR is hydrogen or a pharmaceutically acceptable base salt thereof.

Particularly preferred species of the invention are those compoundshaving the names:

7-(3-(aminomethyl)pyrrolidin-1-yl)-1-ethyl-6-fluoro-8-trifluoromethyl-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid,

7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

1-cyclopropyl-7-[3-[1-(ethylamino)ethyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[1-methyl-1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

7-[3-(aminomethyl)-1-pyrrolidinyl]-1-cyclopropyl]-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

1-ethyl-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-[3-[(methylamino)methyl]-1-pyrrolidinyl]-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

1-ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

1-cyclopropyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

7-(3-amino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid,

7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid, and

7-[3-(1-amino-1methylethyl)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid.

Another aspect of the present invention is a novel process for preparingcompounds of formula I ##STR10## wherein Z, Y, R₁, and R₂ are as definedabove. The process is fully described hereinafter.

Certain novel intermediates of the process are also included in thepresent invention. They include:

3-bromo-2,5,6-trifluorobenzoic acid,

1-bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene,

2,4,5-trifluoro-3-(trifluoromethyl)benzoic acid,

ethyl 2,4,5-trifluoro-β-oxo-3-(trifluoromethyl)benzenepropanoate,

1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid, ethyl ester, or

ethyl1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylate.

The invention also includes a pharmaceutical composition which comprisesan antibacterially effective amount of a compound of formula I or apharmaceutically acceptable salt thereof in combination with apharmaceutically acceptable carrier.

The invention further includes a method for treating bacterialinfections in a mammal which comprises administering an antibacteriallyeffective amount of the above defined pharmaceutical composition to amammal in need thereof.

DETAILED DESCRIPTION

The compounds of the invention having the formula ##STR11## wherein thesubstituents are as defined above are capable of forming bothpharmaceutically acceptable acid addition and/or base salts. Base saltsare formed with metals or amines, such as alkali and alkaline earthmetals or organic amines. Examples of metals used as cations are sodium,potassium, magnesium, calcium, and the like. Also included are heavymetal salts such as for example silver, zinc, cobalt, and cerium. Suchheavy metal salts are effective in the treatment of burns especiallywhen applied to the affected surface of a burn victim either directly orin combination with a physiologically acceptable carrier such as a waterdispersible, hydrophilic carrier. Examples of suitable amines areN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine, and procaine.

Pharmaceutically acceptable acid addition salts are formed with organicand inorganic acids.

Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, lactic, citric, oxalic, malonic,salicylic, malic, gluconic, fumaric, succinic, ascorbic, maleic,methanesulfonic, and the like. The salts are prepared by contacting thefree base form with a sufficient amount of the desired acid to produceeither a mono or di, etc salt in the conventional manner. The free baseforms may be regenerated by treating the salt form with a base. Forexample, dilute solutions of aqueous base may be utilized. Diluteaqueous sodium hydroxide, potassium carbonate, ammonia, and sodiumbicarbonate solutions are suitable for this purpose. The free base formsdiffer from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents, but the salts areotherwise equivalent to their respective free base forms for purposes ofthe invention. Use of excess base where R' is hydrogen gives thecorresponding basic salt.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms. In general, the solvatedforms, including hydrated forms and the like are equivalent to theunsolvated forms for purposes of the invention.

The alkyl groups contemplated by the invention comprise both straightand branched carbon chains of from one to about four carbon atoms exceptwhen specifically stated to be greater than four carbon atoms.Representative of such groups are methyl, ethyl, propyl, isopropyl, andthe like.

The cycloalkyl groups contemplated by the invention comprise thosehaving three to six carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

The term alkanoyl is intended to include ##STR12## groups wherein R¹ isan alkyl of from one to three carbon atoms.

The hydroxyalkyl groups contemplated by the invention comprise thosehaving two to four carbon atoms such as 2-hydroxyethyl, 2- or3-hydroxypropyl, or 2-, 3-, or 4-hydroxybutyl.

The alkoxy groups contemplated by the invention comprise both straightand branched carbon chains of from one to about six carbon atoms unlessotherwise specified. Representative of such groups are methoxy, ethoxy,propoxy, i-propoxy, t-butoxy, hexoxy, and the like.

The term, haloalkyl, is intended to include halogen substituted straightand branched carbon chains of from two to four carbon atoms. Thoseskilled in the art will recognize that the halogen substituent may notbe present on the α-carbon atom of the chain. Representative of suchgroups are β-fluoroethyl, β-chloroethyl, β,β-dichloroethyl,β-chloropropyl, β-chloro-2-propyl, -iodobutyl, and the like.

The term halogen is intended to include fluorine, chlorine, bromine, andiodine unless otherwise specified.

Certain compounds of the invention may exist in optically active forms.The pure D isomer, pure L isomer as well as mixtures thereof; includingthe racemic mixtures, are contemplated by the invention. Additionalasymmetric carbon atoms may be present in a substituent such as an alkylgroup. All such isomers as well as mixtures thereof are intended to beincluded in the invention. Certain side chains may contain more than onechiral center. In these cases the diastereoisomers may be separated andutilized individually. All such mixtures and separated mixtures arecontemplated by the invention.

A novel process of this invention is for preparing compounds of formulaI ##STR13## which comprises (a) carboxylating1-bromo-2,4,5-trifluorobenzene forming 3-bromo-2,5,6-trifluorobenzoicacid,

(b) fluorinating the carboxylic acid group of the above compound forming1-bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene,

(c) carboxylating the bromine position on the above compound forming2,4,5-trifluoro-3-(trifluoromethyl)benzoic acid,

(d) reacting the above benzoic acid compound with a chlorinating agent,an alkyl hydrogen malonate, and n-butyl lithium forming an alkyl2,4,5-trifluoro-β-oxo-3-(trifluoromethyl)benzenepropanoate product,

(e) reacting the above product with alkyl orthoformate and aceticanhydride and then with a primary alkyl amine forming alkylα-(N-alkylaminomethylene)-2,4,5-trifluoro-β-oxo-3-(trifluoromethyl)benzenepropanoate,

(f) cyclizing the above compound by reacting it with a base in a solventforming alkyl 1-alkyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylate,

(g) deesterifying the above carboxylate forming the correspondingcarboxylic acid, and

(h) reacting the above carboxylic acid with a secondary amine to form acompound of formula I and convert, if desired, to a pharmaceuticallyacceptable acid addition or base salt thereof.

The following secondary amines may be used in step h above to form acompound of formula I which may be converted, if desired, to apharmaceutically acceptable acid addition or base salt thereof:##STR14##

The process is illustrated but not limited by Scheme I below. ##STR15##

A novel process of the instant invention comprises lithiating andsubsequently carboxylating 2,4,5-trifluorobromobenzene (Aldrich) to formthe compound 3-bromo-2,5,6-trifluorobenzoic acid. Various lithiatingagents such as a lithium dialkylamide, for example lithiumdiisopropylamide, and carbon dioxide in diethyl ether may be used. Thereaction proceeds at temperatures from about -40° to -100° C.,preferably from about -60° to -80° C. Possible solvents include but arenot limited to ether, dimethoxy ethane and tetrahydrofuran. Thepreferred solvent is tetrahydrofuran.

The carboxylic acid group of the 3-bromo-2,5,6-trifluorobenzoic acid istreated with a fluorinating agent such as, for example, seleniumtetrafluoride or sulphur tetrafluoride and hydrogen fluoride forming thecompound 1-bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene. Thereaction proceeds for from about one to forty-eight hours attemperatures of about 80° to 150° C. Preferably the reaction time isfrom about six to eight hours at temperatures from about 120° to 140° C.

Subsequently the bromine group of the above compound is treated with acarboxylating agent forming the compound2,4,5-trifluoro-3-(trifluoromethyl)benzoic acid. Possible carboxylatingagents include but are not limited by n-butyl lithium and carbondioxide, Mg and either CO₂ or a chloroformate followed by esterhydrolysis, or other organolithium such as MeLi or t-butyl followed byan anhydrous halide salt of a less electropositive metal, then followedeither by CO₂ or a chloroformate derivative, which would be subsequentlyhydrolysed; preferably n-butyl lithium and carbon dioxide are used. Thisportion of the process proceeds at temperatures from about -40° to -100°C. in ether or tetrahydrofuran. Temperatures from about -70° to -80° arepreferred. Alternatively, displacement of bromine by CuCN/DMF at60°-140° C., followed by hydrolysis in strong acid.

The benzoic acid formed above is then treated with a chlorinating agent,an alkyl hydrogen malonate and n-butyl lithium forming the desired alkyl2,4,5-trifluoro-β-oxo-3-(trifluoromethyl)benzenepropanoate. Variouschlorinating agents will be useful such as, for example thionylchloride, POCl₃, PCl₃, and PCl₅. Brominating agents are also possiblesuch as, for example, SOBr₂. Thionyl chloride is the preferred agentused with a dianion of a malonate, such as ethyl hydrogen malonate. Thereaction proceeds at temperatures of from about -40° to -100° C.;preferably from about -70° to -85° C.

The above propanoate is reacted with an alkyl orthoformate and aceticanhydride and subsequently with a primary alkylamino forming an ethyl(N-(cyclo)alkylaminomethylene)-3-oxo-3-aryl propanoate derivative (5b).The reactants are preferably ethyl orthoformate and cyclopropylamine orethylamine. The reaction proceeds for about one to six hours at reflux.

The above seco quinolone product was reacted with a base in an organicsolvent to cyclize the compound forming alkylN-alkyl-6,7-difluoro-8-trifluoromethylquinol-4-one-3-carboxylate. Apreferred base is an alkali hydride such as sodium hydride or tertiaryamine such as triethylamine and solvents includes but are not limited tot-butanol, DMSO, tetrahydrofuran. The reaction occurs at temperaturesfrom about -20° to 100° C.

The quinoline is then deesterified forming the corresponding carboxylicacid. Useful reactants are chlorotrimethylsilane and sodium iodide inacetonitrile. Hydrogen chloride in acetic acid is also useful. Thedeesterification occurs at reflux which in the case of acetonitrilewould be at about 80° C. The reaction time is from two to six hours.

The resulting quinoline is reacted with a secondary amine forming adesired compound of the present invention and converting it, if desired,to a pharmaceutically acceptable acid addition or base salt thereof.Possible reaction solvents include acetonitrile, DMSO, or DMF. Thereaction proceeds at between 0° and 100° for from about two to tenhours. Secondary amines reacted with the compound may be protected asnecessary. Possible secondary amines include but are not limited to allthe secondary amines described herein by Z.

The compounds of the invention can be prepared and administered in awide variety of oral, parenteral and topical dosage forms. It will beobvious to those skilled in the art that the following dosage forms maycomprise as the active component, either a compound of formula I or acorresponding pharmaceutically acceptable salt of a compound of formulaI.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets, suppositories, andointments. A solid carrier can be one or more substances which may alsoact as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, or tablet disintegrating agents; it can also be anencapsulating material. In powders, the carrier is a finely dividedsolid which is in admixture with the finely divided active compound. Inthe tablet the active compound is mixed with carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired. The powders and tablets preferably containfrom 5 or 10 to about 70 percent of the active ingredient. Suitablesolid carriers are magnesium carbonate, magnesium sterate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and thelike. The term "preparation" is intended to include the formulation ofthe active compound with encapsulating material as carrier providing acapsule in which the active component (with or without other carriers)is surrounded by carrier, which is thus in association with it.Similarly, cachets are included. Tablets, powders, cachets, and capsulescan be used as solid dosage forms suitable for oral administration.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection. Such solutions are prepared so as to beacceptable to biological systems (isotonicity, pH, etc.). Liquidpreparations can also be formulated in solution in aqueous polyethyleneglycol solution. Aqueous solutions suitable for oral use can be preparedby dissolving the active component in water and adding suitablecolorants, flavors, stabilizing, and thickening agents as desired.Aqueous suspension suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, i.e.,natural or synthetic gums, resins, methyl cellulose, sodiumcarboxymethyl cellulose, and other well-known suspending agents.

Ointment preparations contain heavy metal salts of a compound of formulaI with a physiologically acceptable carrier. The carrier is desirably aconventional water-dispersible hydrophilic or oil-in-water carrier,particularly a conventional semi-soft or cream-like water-dispersible orwater soluble, oil-in-water emulsion which may be applied to an affectedburn surface or infected surface with a minimum of discomfort. Suitablecompositions may be prepared by merely incorporating or homogeneouslyadmixing finely divided compounds with the hydrophilic carrier or baseor ointment.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, for example, packeted tablets, capsules, powders in vialsor ampules, and ointments in tubes or jars. The unit dosage form canalso be a capsule, cachet, tablet, gel or cream itself or it can be theappropriate number of any of these packaged forms.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from 1 mg to 100 mg according to the particularapplication and the potency of the active ingredient.

In therapeutic use as agents for treating bacterial infections thecompounds utilized in the pharmaceutical method of this invention areadministered at the initial dosage of about 3 mg to about 40 mg perkilogram daily. A daily dose range of about 6 mg to about 14 mg perkilogram is preferred. The dosages, however, may be varied dependingupon the requirements of the patient, the severity of the conditionbeing treated, and the compound being employed. Determination of theproper dosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

The following nonlimiting examples illustrate methods for preparing thecompounds of the invention.

EXAMPLE 1 3-Bromo-2,5,6-trifluorobenzoic acid

n-Butyl lithium (2.6M in hexanes, 32 mL, 84 mmol) was added over 10minutes to a solution of diisopropylamine (8.89 g, 88 mmol) in THF (80mL) stirred under N₂ at 0° C. After a further 10 minutes at 0°, thesolution was transferred by catheter over 40 minutes to a solution of2,4,5-trifluorobromobenzene (16.88 g, 80 mmol) in THF (200 mL) stirredunder N₂ at -78°. After a further 15 minutes the solution was blownthrough a catheter over ≈2 minutes onto a slurry of CO₂ (≈200 mL) inether (400 mL) with vigorous stirring. When the CO₂ evaporated theslurry was washed with dilute HCl (1M, 200 mL) and water (100 mL). Theorganic phase was extracted with dilute NaOH (0.5M, 2×100 mL). Theaqueous phase was washed with ether (100 mL) and made acidic (12N HCl, 9mL). The aqueous phase was extracted with ether (2×100 mL), and thecombined organic phases were washed with water (100 mL), saturated brine(100 mL) and dried (MgSO₄). The solvent was removed under reducedpressure to give 3-bromo-2,5,6-trifluorobenzoic acid (17.25 g, 84.5%) aswhite microcrystalline needles; mp 114°-6° (sublimation). Nmr (CDCl₃) δ10.73 (1H, s, OH), 7.54 (1H, d of t, J_(d) =6 Hz, J_(t) =9 Hz aromatic).

EXAMPLE 2 1-Bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene

3-Bromo-2,5,6-trifluorobenzoic acid (16.92 g, 66 mmol) was heated withSF₄ (60 g) and HF (30 g) in a stainless steel bomb at 120° for 8 hours.When the reaction cooled to 25° the volatiles were vented through KOHtraps, and when gas evolution ceased the vessel was extracted with CH₂Cl₂ (150 mL). This solution was washed with diluted NaHCO₃ solution(saturated/2, 50 mL), saturated brine (50 mL), and dried (MgSO₄). Thesolvent was removed by distillation through a 15 cm Vigreux column, andthe residue was distilled under N₂ through a shortpath stillhead at147°-150° to give 1-bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene(15.79 g, 83%) as a pale yellow oil. Nmr (CDCl₃) δ 7.67 (1H, d of t,J_(d) =6 Hz, J_(t) =8.1 Hz, aromatic). Ir (film) 1495, 1315, 1211, 1165,1149, 919. M.S. 280 (97 ⁸¹ BrM.sup.⊕), 278 (100, ⁷⁹ BrM.sup.⊕).

EXAMPLE 3 2,4,5-Trifluoro-3-(trifluoromethyl)benzoic acid

A solution of n-butyl lithium (2.6M in hexanes, 9.6 mL, 25 mmol) wasadded dropwise through an addition funnel over 15 minutes to a solutionof 1-bromo-2,4-5-trifluoro-3-(trifluoromethyl)benzene (7.00 g, 25 mmol)in ether (100 mL) stirred under N₂ at -78°. After 5 minutes the rxnmixture was rapidly blown by catheter onto a suspension of dry ice (100g) in ether (100 mL). After 5 minutes TFA (2 mL) was added to this. Whenthe solution had warmed up to 20° C., it was washed with diluted HCl(0.5M, 20 mL), and extracted with dilute base (0.5N, 2×50 mL). Thecombined basic extracts were washed with ether (25 mL), made acidic withconcentrated HCl (≈4 mL) and extracted with ether (3×50 mL). Thecombined ethereal extracts were washed with water (50 mL), saturatedbrine (50 mL) and dried (MgSO₄). The solvent was removed under reducedpressure to give 2,4,5-trifluoro-3-(trifluoromethyl)benzoic acid (4.21g, 69%) as white microscopic needles; mp 87°-90° C. Nmr (CDCl₃) δ 11.80(1H, br s, OH), 8.05 (1H, d of t, J_(d) =6 Hz, J_(t) =9 Hz, aromatic).IR (KBr) 1721, 1636, 1511, 1464, 1424, 1328, 1256, 1154, 928 cm⁻¹.M.sup.⊕ 244 (56).

EXAMPLE 4 Ethyl2,4,5-trifluoro-β-oxo-3-(trifluoromethyl)benzenenpropanoate

2,4,5-Trifluoro-3-(trifluoromethyl)benzoic acid (0.49 g, 2 mmol) wasrefluxed in SOCl₂ (1 mL) under N₂ for 21/2 hours. The volatiles wereremoved under reduced pressure, and azeotroped further with toluene (5mL). The residual light yellow-brown oil was dissolved in THF (5 mL),and cooled to -78° under N₂ with stirring.

n-Butyl lithium (3.1 mL, 8 mmol, 2.6M in hexanes) was added dropwise toa solution of ethyl hydrogen malonate (0.53 g, 4 mmol) and bipyridyl (1mg) in THF (5 mL) stirred at -78° under N₂, until pink coloration (≈1.5mL). The reaction mixture was stirred on an ice salt bath and theremainder of the butyl lithium was added, giving a pink color. Thissuspension was then added dropwise via syringe over 10 minutes to the-78° solution of the acid chloride, to form a nearly clear bright yellowsolution. After 2 hours at -78° the rxn mixture was quenched by rapidaddition of dilute HCl (1M, 8 mL). When the mixture had melted, it waspoured onto water (25 mL), and extracted with ether (3×10 mL). Thecombined organic extracts were washed with water (10 mL), saturatedNaHCO₃ (10 mL), saturated brine (10 mL) and dried (MgSO₄). The solventwas removed under reduced pressure to giveethyl-3-oxo-3-(2,4,5-trifluoro-3-(trifluoromethyl)phenyl)propanoate(0.52 g, 83%) as a golden-brown oil. Nmr (CDCl₃) δ 7.91 (1H, sl br, d oft, J_(d) =6 Hz, J_(t) =9 Hz, aromatic), 5.74 (≈1/3H, br s, vinyl ofenol), 4.15 (2H, q, J=7 Hz, OCH₂), 3.90 (≈11/3H, d, J=4 Hz, methylene αto CO), 1.1-1.5 (≈4H, 2 overlapping t+broad m, CH_(3s)), 0.7-1.0 (≈1H,m, Bu n related).

EXAMPLE 5 Ethyl1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylate

Ethyl 2,4,5-trifluoro-β-oxo-3-(trifluoromethyl)benzenepropanoate (0.52g, 1.67 mmol)ethyl orthoformate (0.45 g, 3 mmol) and acetic anhydride(0.41 g, 4 mmol) were refluxed under N₂ for 90 minutes. The volatileswere removed under reduced pressure, and the residual brown oil (0.59 g)was mixed with cyclopropylamine (0.12 g, 2 mmol) in THF (5 mL) stirredunder N₂ at 20° C. After 90 minutes the volatiles were removed underreduced pressure to give a waxy brown solid. This was dissolved in THF(5 mL) under N₂ at 20° with stirring, and sodium hydride (60% oilsuspension, 0.10 g, 2.5 mmol) was added. After 15 minutes the reactionwas quenched by addition of acetic acid (1 mL). The reaction mixture wasdiluted with CHCl₃ (25 mL) and washed with water (2×25 mL) and dried(MgSO₄). The solvent was removed under reduced pressure to give areddish-brown solid, which was purified by preparative tlc on silica(2×20 cm) eluting with 5% MeOH in CHCl₃. The major band (r_(f) =0.66)was extracted with CHCl₃ /MeOH, and the solvent was removed underreduced pressure to give ethylN-cyclopropyl-6,7-difluoro-8-trifluoromethyl-quinol-4-one-3-carboxylate(0.14 g, 23%) as an ochre solid; mp 174°-9° C. Nmr (CDCl₃) δ 8.68 (1H,s, H2), 8.42 (1H, t, J=9 Hz, H5), 4.40 (2H, q, J=6.1 Hz, OCH₂),3.92-4.07 (1H, m, NCH), 1.41 (3H, t, J=6.1 Hz, CH₃), 1.15-1.25 (2H, m,cyclopropyl), 0.67-0.75 (2H, m, cyclopropyl). Ir (KBr) 1738, 1638, 1612,1470, 1311, 1297, 1269, 1190, 1180, 1162, 1151, 1074, 897, 805. M.sup.⊕361 (10).

EXAMPLE 61-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid

Chlorotrimethylsilane (0.54 g, 5 mmol) ethyl1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluorophenyl)-3-quinolinecarboxylate(0.76 g, 2.1 mmol) and NaI (0.75 g, 5 mmol) were stirred in refluxingCH₃ CN (10 mL) under N₂ for 8 hours. On cooling water (30 mL) was addedand the mixture was extracted with EtOAc (2×20 mL). The combinedextracts were washed with water (2×10 mL), saturated brine (12 mL) anddried (MgSO₄). The solvent was removed under reduced pressure, and theresidual brown solid (0.74 g) was dissolved in hot CHCl₃, andprecipitated with ether at 0° C. to give1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid (0.43 g, 62%) as yellow needles; mp 243.5°-244.5° C. C₁₄ H₈ F₅ NO₃requires C, 50.45; H, 2.40 N, 4.20 F, 28.53%. Found C, 50.10; H, 2.27;N, 4.03 F, 28.08%. Nmr (DMSO) δ 13.5-14.5 (1H, br s, OH), 8.98 (1H, s,H2), 8.53 (1H, t, J=9.2 Hz, H5), 4.15-4.25 (1H, m, NCH), 1.05-1.15 (2H,m, CH₂), 0.80-0.88 (2H, m, CH₂). Ir (KBr) 1724, 1630, 1618, 1565, 1505,1467, 1429, 1398, 1337, 1324, 1283, 1269, 1199, 1180, 1172, 1161, 1130,1093, 1051, 1023, 922, 910, 808, 743 cm⁻¹. Ms 334 (5 MH⁺) 333 (13, M⁺).

EXAMPLE 71-Cyclopropyl-7-(3-((N-ethylamino)methyl)-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid

1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid (0.20 g, 0.61 mmol) 3-((N-ethylamino)methyl)pyrrolidine (0.20 g,1.6 mmol) and NEt₃ (0.20 g, 2 mmol) were refluxed with stirring under N₂in CH₃ CN (2 mL) for 2 hours. When the reaction mixture had cooled to20° the yellow solid was collected by vacuum filtration, washed withwater (5 mL) and ether (5 mL), and then dried at 110°/0.2 mm to give1-cyclopropyl-7-(3-((N-ethylamino)methyl)pyrrolidinyl)-6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid (0.26 g, 97%) as a light yellow solid; mp 239°-241° C. C₂₁ H₂₃ N₃O₃ F₄ requires C, 57.14; H, 5.22; N, 9.52; F, 17.23%. Found, C, 56.77;H, 4.98; N, 9.34; F, 16.95%. Nmr (TFA) δ 9.37 (1H, s, H2), 8.09 (1H, d,J=13.8 Hz, H5), 7.2-7.5 (2H, br s, NH⁺ ₂), 4.45-4.55 (1H, m, H1pyrrolidinyl), 4.1-4.4 (2H, m, H5 pyrrolidinyl), 3.9-4.1 (2H, m, H1cyclopropyl+pyrrolidinyl), 3.3-3.65 (4H, m, CH_(2s) ethylaminomethyl),2.9-3.1 (1H, m, H3 pyrrolidinyl), 2.5-2.65 (1H, m, H4 pyrrolidinyl),1.9-2.1 (1H, m, H4 pyrrolidinyl), 1.5-1.8 (5H, m and t, J=7.1 Hz,cyclopropyl and CH₃), 0.95-1.4 (2H, m, cyclopropyls). Ir (KBr) 1629,1456, 1360 cm⁻¹. MS 442 (4, M H.sup.⊕), 441 (4, M.sup.⊕).

We claim:
 1. A compound of the formula ##STR16## wherein R₁ is hydrogen,an alkyl of from one to six carbon atoms or a cation;R₂ is alkyl of fromone to four carbon atoms, vinyl, haloalkyl or hydroxyalkyl of from oneto four carbon atoms or cycloalkyl of from three to six carbon atoms, Yis hydrogen, fluoro, or amino; Z is ##STR17## R₃ is hydrogen, alkyl offrom one to four carbon atoms or a cycloalkyl of from three to sixcarbon atoms; R₅ and R₆ are each independently hydrogen or alkyl of fromone to three carbon atoms; or a pharmaceutically acceptable acidaddition or base salt thereof.
 2. A compound according to claim 1wherein R₂ is ethyl, vinyl, 2-fluoroethyl, difluoroethyl, orcyclopropyl.
 3. A compound according to claim 1 wherein Z is ##STR18##wherein R₃ is hydrogen, methyl, ethyl, n-propyl, or 2-propyl, R₅ and R₆are hydrogen, methyl, or ethyl.
 4. A compound according to claim 1wherein R is hydrogen or a pharmaceutically acceptable base saltthereof.
 5. A compound according to claim 1 and being1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-8-(trifluoromethyl)-3-quinolinecarboxylicacid.
 6. A compound according to claim 1 and being1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-8-(trifluoromethyl)-3-quinolinecarboxylicacid.
 7. A compound according to claim 1 and being1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid.
 8. A compound according to claim 1 and being1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid.
 9. A compound according to claim 1 and being1-cyclopropyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylicacid.
 10. A pharmaceutical composition comprising an antibacteriallyeffective amount of a compound as claimed in claim 1 together with apharmaceutically acceptable carrier.
 11. A method of treating bacterialinfections in mammals which comprises administering to said mammal apharmaceutical composition as claimed in claim 10 in unit dosage form.